title: NSAID, aspirin delays gastric ulcer healing with reduced accumulation of CXCR4(+)VEGFR1(+) cells to the ulcer granulation tissues.
abstract: BACKGROUND
  Ulcer healing is a complex process, which involves cell migration, proliferation, angiogenesis and re-epithelialization. Several growth factors have been implicated in this process but the precise mechanism is not well understood. This study examined the involvement of VEGFR1 signaling in the gastric ulcer healing.
  
  
  METHODS
  Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter.
  
  
  RESULTS
  The healing of acetic acid induced ulcers and the progenitor cells expressing CXCR4(+)VEGFR1(+) cell were significantly delayed in NSAID treated mice. The areas of the ulcer was significantly suppressed in tyrosine kinase-deficient VEGFR1 mice (VEGFR1TKKO) compared with wild type (WT) mice. The plasma level of SDF-1 and stem cell factor (SCF) and bone marrow level of pro-matrix metallopeptidase 9 (pro-MMP-9) were significantly reduced in VEGFR1TKKO mice. In VEGFR1 TKKOmice, the progenitor cells expressing CXCR4(+)VEGFR1(+) cell from bone marrow and the recruitment of these cells in healing ulcer were suppressed. Furthermore, VEGFR1 TKKO mice treated with NSAID did not suppress gastric ulcer healing compared to vehicle mice. These results suggested that NSAID suppressed VEGFR1 TK signaling plays a critical role in ulcer healing through mobilization of CXCR4(+)VEGFR1(+) cells.
  
  
  CONCLUSIONS
  VEGFR1 signaling is required for healing of NSAID induced gastric ulcer and angiogenesis with increased recruitment of CXCR4(+)VEGFR1(+) cells to the ulcerative lesion.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan; Department of Gastroenteology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, 252-0374 Sagamihara Kanagawa, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Sato
authors.forename: Hideki
authors.initials: H
authors.lastname: Amano
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Koji
authors.initials: K
authors.lastname: Eshima
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Minamino
authors.forename: Takako
authors.initials: T
authors.lastname: Ae
authors.forename: Chikatoshi
authors.initials: C
authors.lastname: Katada
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohno
authors.forename: Kanako
authors.initials: K
authors.lastname: Hosono
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D019342:Acetic Acid; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001241:Aspirin / Q000009:adverse effects*; D054377:Chemokine CXCL12 / Q000097:blood; D004792:Enzyme Precursors / Q000378:metabolism; D006097:Granulation Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000097:blood; D013276:Stomach Ulcer / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D004792:Enzyme Precursors; D019718:Receptors, CXCR4; D019089:Stem Cell Factor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9; D019342:Acetic Acid; D001241:Aspirin
keywords: Angiogenesis; NSAD; Stomach; Ulcer; VEGF